Tertiary dialkylamino propanols



TERTIARY DIALKYLAMINO PROPANOLS John Joseph Denton, Somerville, N. J.,assignor to American Cyanamid Company, New York, N. Y., a corporation ofMaine No Drawing. Application November 3, 1949, Serial No. 125,382

3 Claims. (Cl. 260570.6)

The present invention is concerned with a novel group of synthetic,physiologically-active, basic tertiary alcohols. As such, thisapplication constitutes a continuation-in-part of my copendingapplication Serial No. 691,882, filed August 20, 1946, and nowabandoned.

Many different synthetic compounds, pharmacologically-active asanti-spasmodics and local anesthetics, have been synthesized from timeto time. The more active and apparently useful of these compounds have,in general, comprised fairly complex molecules containing at least oneester grouping. This grouping was generally considered essential on thebasis of analogy to the naturallyoccurring extractives which wereconsidered esters of tropic or pseudo-tropic acids.

Unfortunately, for one reason or another, many if not most of thesecompounds were not wholly satisfactory. Among other factors, thepresence-of the ester grouping introduces a chemically labile structurewhich adds to the instability of the molecule. This instability createsdifiiculty in the laboratory, making the preparation, purification, andhandling of the materials extremely difficult. Further, modification mayoccur in several ways in the animal organism in which the compound isattempted to be used. For example, the compound may break down intoother compounds which are ineffectual, or which are irritating, or whichmay even be highly toxic.

It is, therefore, the principal object of the present invention todevelop a series of compounds which are physiologically active,especially as anti-spasmodics. In so doing, it is a further and addedobject to' develop materials which are not subject to the objectionablebreakdown which so frequently characterized the more active of thepreviously-known, synthetic, pharmacologically-active esters.

In the accomplishment of these objects in accordance with the presentinvention, the surprising fact has been found that the ester groupingpreviously considered essential in the prior art is quite unnecessary.It has been found in accordance with the present invention that thedesirable characteristics are evidenced by a group of basic nitrogenoustertiary alcohols containing no ester groupmg.

In particular the present application contemplates the basic tertiaryalcohols of the general formula in which PH, Alk1 and Alkz have thevalues noted immediately below.

Alk1 and PH by their location on the molecule may be interchangeable.Alkl may be an alkyl radical of from about two to six carbon atoms. Alkzis a methyl or ethyl radical. PH may be a phenyl tolyl, xylyl, or amonoor dihydroxy, methoxy, chloro-or bromo-substituted phenyl radical.

From the foregoing it will be seen that the compounds of the presentinvention may vary in scope and structure.

' 4 -methoxyphenyl.

. pure,

ice

Typical illustrative compounds of the type having the structural formulaand values noted above are those contained in the following table ofcompounds in which PH, Alkl and Alkz have the designated values.

TABLE I Alk;

dimethylamino.

dlethylamino.

dlmethylamlno.

2,4-methoxyphenyl. 2,4-dihydroxyphenyl. 2,5-dimethoxyphenyl.

Some of the basic tertiary alcohols of the present invention arecrystalline solids. Others, however, are so difficultly crystallizableas to appear to be permanent oils and some appear actually to bepermanent oils. The crystalline compounds appear to be free from colorwhen Most ofthe alcohols are relatively insoluble in water but arereadily soluble in ether and in alcohol-ether mixtures. v

The alcohols readily form crystalline addition salts, such as thehydrochloride, nitrate, citrate and the like, by reacting the alcoholwith the desired acid in the ordinary way in solution. Thehydrochlorides, for example, are readily formed and are soluble inaqueous solution. In some cases the water-solubility is so marked thatthe salts are extremely hygroscopic and in crystalline form must be Icarefully handled. They possess the markedly useful I tallization.

property in aqueous solution of remaining stable over long periods oftime. Quaternary salts such as the methobromide, methiodide,methochloride, ethiodide and ethobro mide form readily. Some crystallizewith water of crys- The quaternary salts appear to have about the sameactivity as the addition salts and considerably longer action. Some alsoshow mydriatic activity. The salts therefore possess marked utility forpharmacological experiment.

It is surprising that the basic tertiary alcohols of this inventionshould possess antispasmodic properties in view of the previouslyconsidered desirability of the ester grouping. Especially is this asurprising feature in view of the fact that secondary alcohols ofsimilar structure, for example, 3-(l-piperidyl)-1-phenyl-l-propanol andthe like possesses no' appreciable pharmacological activity either asanesthetics or spasmolytics. According to the present invention,therefore, a novel synthesis has been developed which is general andmore effective in operation. This process involves the addition of asuitable Grignard reagent to the proper basic ketone in the presence ofa suitable solvent for both. Heating for sufiicient time to complete thereaction, followed by hydrolysis produces the desired basic tertiaryalcohol. A typical illus-- tration of the reaction may be indicated asfollows:

Alk:

PrrooomoH,-N I

Alka

PH OMgBr /Al.kz CCH2CH2N Alk; Alkz PH OH Alka H2O CH2-CH2N Alk A1112Since the first stage in this reaction must be carried out underconditions which are not conducive to hydrolysis, a dialkyl ether, forexample, diethyl or dibutyl ether and the like, has been found to be awholly satisfactory solvent.

Several precautionary measures should be observed for best operation.Since the first step addition of the Grignard reagent, must be carriedout under conditions which are not conducive to hydrolysis, the solvent,whether an ether, a benzene-pyridine mixture or the like, should beessentially anhydrous.

Choice of the particular halogen used in the Grignard reagent may havecertain advantages in individual cases. In general, the chloride,bromide and iodide may all be used. In some cases, however, the reagentitself apparently tends to form an insoluble complex with the ketone. Insuch cases the chloride appears to produce the least insoluble complexesand therefore may be preferable. For a similar reason, in such cases theuse of a higher boiling solvent such as dibutyl ether may become preferable in order to utilize increased temperature and thereby improve thesolubility.

The amount of Grignard reagent chosen also has an effect on the yield.Apparently this again may be due to the formation of a complex. Thelatter is believed to form but to break down on hydrolysis. For thisreason it appears that some of the reagent is not available for furtherreaction. In any case aconsiderable increase over an equimolecularamount of the Grignard reagent ordinarily produces a definitelyincreased yield. Above about two molecular equivalents, however, furtherincrease in the amount used produces a markedly diminishing return.About two mols of Grignard reagent per mol of ketone appears to be thepreferable range.

k Preparation of the products of the present invention will beillustrated in conjunction with the following examples, which are to betaken as illustrative only and not by way of limitation. All parts areby weight unless otherwise noted.

EXAMPLE 1 I -dimezhy[amino-S-phenyl-3-pentanol To a solution ofethylmagnesium bromide (prepared from 37.5 parts of magnesium turnings,164 parts ethyl bromide and 750 parts by volume of dibutyl ether) isadded a dry solution consisting of 129 parts ofomegadimethylarninopropiophenoneand 500 parts by volume of dibutyl otherat a rate such as to keep the temperature of the reaction mixture at40-50 C. while it is being stirred rapidly. After thedimethylaminopropiophenone has been added, the mixture is stirred andheated at 40-50 C. for 1 /2 hours and then allowed to stand-at roomtemperature until reaction substantially ceases. A solution consistingof 82.1 parts of hydrogen chloride dissolved in 450 parts of water isadded slowly to the reaction mixture while it is being stirredvigorously and cooled. The resultant solid is removed by filtration andis redissolved in 600 parts of water. Ammonium hydroxide solution isadded until the mixture becomes alkaline. The l-dimethylamino-3-phenyl-3-pentanol which precipitates is collected on a filter andpurified by recrystallization from dilute ethanol. It melts at 45.446.2C.

EXAMPLE 2 1-dimethylamin0-3-phenyl-3-pentan0l hydrochloride1-dimethylarnino3-phenyl-3-pentano1 prepared in accordance with Example1 is dissolved in diethyl ether. This ether solution is treated with dryhydrogen chloride gas until the mixture becomes acidic to Congo red. Thewhite crystalline product which forms during acidification is collectedby filtration and purified by recrystallization to 1-dimethylamino3-phenyl-3-pentanol hydrochloride melting at 125.2l25.8 C. (uncorrected)after previous sintering at 124.7 C.

EXAMPLE 3 1-dimethylamina-3-phenyl-3-pentdnol ethobromide On standingfor three days, a solution of 5 parts of 1-dimethylamino-B-phenyl-3-pentanol, 13.6 parts of ethyl bromide, and 20parts by volume of nitromethane, was diluted with parts by volume ofether. After dilution the mixture deposits the above ethobromide.Recrystallization of this material from an alcohol-ether mixture gives asolid melting at 1lO.2-117 C., which on analysis, was found to contain2.2 percent moisture.

EXAMPLE 4 1dimethylamina-6-methyl-3-phenyl-3-heptanol Whenisoamylmagnesium bromide is substituted for the ethylmagnesium bromidein the procedure for making l-dimethylamino-3-phenyl-3-pentanol,1-dimethylamino-6- methyl-3-phenyl-3-heptanol is formed.

EXAMPLE 5 1-aiethylamino-3-ph-enyl-3-pemanol hydrochloride Substitutingomega-diethylaminopropiophenone for the omega-dimethylaminopropiophenoneof Example 1 yields 1 diethylamino 3 phenyl 3 pentanol. Converting thelatter to the hydrochloride according to the process of Example 2 yieldsa salt melting at 167.0-167.5 C.

EXAMPLE 6 I -diethylamin0-3-phenyl-3-pentan0l ethobromide Nine parts ofl-diethylamino-3-phenyl-3-pentanol hydrochloride is dissolved in aminimum amount of water. This solution is made alkaline with dilutecaustic, and the free amine which separates is extracted with ether. The other solution is-dried over anhydrous potassium carbonate, filtered,and the ether evaporated. The residue is treated with 50 parts by volumeof nitromethane and 15 parts by volume of ethyl bromide. After two daysat ordinary temperature, dilution of the solution with 200 parts byvolume of ether causes 1-diethylamino-3-phenyl- 3-pentanol ethobromideto precipitate. It may be further purified, if desired, byrecrystallization from an alcoholacetone mixture. When pure, it melts at173.8176.0

EXAMPLE 7 1-diethylamina-6-methyl-3-phenyl-3-heptanol hydrochloride To asolution of isoamylmagnesium chloride (prepared from 68.2 parts ofmagnesium turnings, 332 parts of isoamyl chloride and 1235 parts byvolume of ether), a solution of 300 parts ofomegadiethylaminopropiophenone in about 500 parts by volume of ethylether is added, with stirring, over a period of about 15 minutes at 5-35C. The reaction mixture is stirred at room temperature until thereaction appears to cease. The mixture is then chilled and treated byslowly adding 840 parts by volume of 5N hydrochloric acid. The solidformed is collected on a filter, dried, dissolved in 7000 parts byvolume of boiling water, the solution being treated with decolorizingcharcoal, filtered, and made alkaline by the addition of ammoniumhydroxide. The oil which separates is extracted with ether and theethereal solution is dried over anhydrous calcium chloride and filtered.When dry hydrogen chloride gas is passed into this ether solution,l-diethylarnino-6-methyl-3-phenyl-3-heptano1 hydro- CzHs .HCI

chloride precipitates as a white solid. The hydrochloride melts at206.7-207.0 C.

From the foregoing examples, the process of preparing the basic tertiaryalcohols of the present invention is believed to be clear. In preparingthe other compounds of this invention, the procedures of theseillustrative examples may be followed. To prepare additional compoundsof the present invention requires only substitution of molecularlyequivalent amounts of the corresponding aryl ketone and/ or theappropriate alkyl Grignard reagent.

The basic tertiary alcohols of this invention may also be prepared bythe addition of aryhnagnesium halides to alkyl Z-dialkylaminoethylketones. The lack of availability of the latter ketones and thedifiiculty of their preparation, however, make the previously describedpreparation by the addition of alkylmagnesium halides to arylZ-dialkylaminoethyl ketones the preferred and more practical method ofsynthesis.

As was noted above, the compounds of the present invention have a numberof desirable properties. However, it is quite surprising that thestructure of the alcohols having the desired properties is sospecifically limited. For example, a general formula including compoundsof the present invention may be written as follows:

PH\OH Alka 3 (0 Hr) r-N Alki Alk:

When so written n represents the number of carbon atoms separating theN(Alk2)2 grouping and the carbon carrying the alcoholic hydroxyl group.The compounds of the present invention are all those in which n is two.Varying n to alter the separation by one more or one less carbon atomgives compounds having much lower or no activity. This is illustrated,for example, in the follow- Antispasmodic Index=LD /EDm, where LD is theintraperitoneai dosage in mice in mg./kg. required to kill 50% of thetest animals and ED is the gammasoi compound per hundred ml. of bathrequired to produce 50% relaxation of a segment of isolated spasticrabbit intestine.

Similarly the desired properties seem to reside only in alcoholscontaining the grouping PH OH I Alki If in this grouping PH is replacedby Aiki, and Alki and Alkz are methyl or ethyl, or as in the presentinvention, the resultant alcohols again have very little or noantispasmodic activity. The activity of such compounds is not sufiicientfor pharmacological utilization. This is illustrated in the followingtable:

Compound Autispasmpdie Number Structure Acnvlty 1 CH3 OH 1CHz-CH2-N(CHz)z 0 GHa O2Hs OH 2 cOH,-OH,N(OH,), 0

PH\OH 3 (]-CH2CH2-N(CH3): 55

CiHr

PH OH 4 --CH2CH2N(C:H5)|

1 Relative activity based on activity of compound 4 as one hundred.

I claim: 1. 1-diethylarnino-3-phenyl-3-pentanol. 2. A compound of thegroup consisting of tertiary amino alcohols of the formula R\|OH /RiC-CH2CH2N\ V Alk R1 wherein R is phenyl, Alk is an alkyl of 2 to carbonatoms and is a lower dialkylamino group and acid addition salts thereof.

3. 1-dimethylamino-3-phenyl-3-pentano1.

References Cited in the file of this patent UNITED STATES PATENTS828,846 Fourneau Aug. 14, 1906 1,978,539 Klarrer et al Oct. 30, 19342,282,907 Ter Horst May 12, 1942 2,411,664 Miescher et a1. Nov. 26, 1946FOREIGN PATENTS 234,785 Switzerland Feb. 16, 1945 240,363 SwitzerlandMay 16, 1946 698,687 France Feb. 3, 1931 OTHER REFERENCES Maire: Bull.Soc. Chim. 41 vol. 3 (1908), pp. 280-86. Campbell: Jour. Amer. Chem.800., vol. 60 (1938), pp. 1372-76.

1. 1-DIETHYLAMINO-3-PHENYL-3-PENTANOL.